Venkatesh Srinivasa

Topical amitriptyline in healthy volunteers

Background and Objectives The antidepressant amitriptyline is used as an adjuvant in the treatment of a variety of chronic pain conditions. This drug interacts with many receptors and ion channels, such as Na+ channels. In a randomized, double-blinded, and placebo-controlled trial, we investigated whether amitriptyline also is capable of providing cutaneous analgesia when applied topically in 14 healthy volunteers. Methods Amitriptyline hydrochloride was prepared as a 45% water/45% isopropanol/10% glycerin solution and titrated to pH 8.5 with sodium hydroxide. Four areas, 2 on each arm, of approximately 1 cm2 each were marked on the ventral aspect of the upper arm. A piece of gauze, placed on each of the marked areas and affixed to the arm with an occlusive plastic dressing, was saturated via syringe with placebo and amitriptyline solutions (10 mmol/L, 50 mmol/L, and 100 mmol/L). After 1 hour, the dressings and gauze were removed. A 16-G blunt needle was used to grade the pain at the marked area once per hour (1 = complete analgesia, 10 = normal pain sensation). Results The analgesic effects of 50 mmol/L and 100 mmol/L solutions of amitriptyline were significantly higher than those of the placebo or the 10 mmol/L solution. However, no significant difference was found between the analgesia provided by the placebo solution versus the 10 mmol/L solution or between the 50 mmol/L versus the 100 mmol/L solution. The only side effect observed was a concentration-dependent redness of the skin. Conclusions Topically applied amitriptyline is effective as an analgesic in humans. Different vehicles may improve its efficacy and decrease the skin redness observed.

Assessment of differential blockade by amitriptyline and its N-methyl derivative in different species by different routes

Background Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep. Methods The Na+ channel–blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH3 cells. Various functions (motor, nociception, proprioception–ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data). Results In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mm N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data. Conclusions Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.

Thromboelastography: where is it and where is it heading?

Thromboelastography (TEG) has been in existence since 1948. However, it is only recently that it has made great strides into the clinical practice arena, where it is being used to assist in the diagnosis and management of coagulation problems during liver transplantation and cardiac surgery and in obstetrics. With the advent of computerization in the last decade, TEG has evolved from a research laboratory tool into a compact, user-friendly process, providing global information on the entire coagulation process. In fact, TEG is the only single test method that provides information on the balance between two important and opposing components of coagulation, namely thrombosis and lysis. The battery of traditional coagulation tests, which include bleeding time, prothrombin time (PT), partial thromboplastin time (PTT), thrombin time, fibrinogen and factor assays, and platelet function studies, are based on the isolated, static end points of standard laboratory tests. They do not take into account the interaction of clotting cascade and platelets in the whole blood. Furthermore, some of these tests can be nonspecific. For example, bleeding time has been shown to be a nonspecific indicator of platelet function. Platelet aggregation tests are expensive, laborious, and difficult to reproduce, and abnormalities cannot be used to predict risk of hemorrhage. The tests that measure clot lysis, which include fibrinogen degradation products, can be elevated in renal and hepatic disease. In contrast, hemostasis is an integrated, interactive, dynamic, and extremely complex process involving coagulation proteins, activators, cellular elements, and inhibitors. TEG measures this interactive dynamic coagulation process from the initial clotting cascade to platelet interaction and clot strengthening (via

The relative toxicity of amitriptyline, bupivacaine, and levobupivacaine administered as rapid infusions in rats.

Intravascular injection of local anesthetics carries the risk of cardiovascular (CV) and central nervous system (CNS) toxicity. Amitriptyline, a tricyclic antidepressant, has local anesthetic potency that is more than that of bupivacaine. In this study, we compared the CV and CNS toxicity of the local anesthetics bupivacaine and levobupivacaine with that of amitriptyline. Twenty-nine Sprague-Dawley rats had their right external jugular vein and carotid artery cannulated under general anesthesia. On Day 2, rats were sedated with midazolam (0.375 mg/kg intraperitoneally) and received rapid infusions of either 1) bupivacaine, levobupivacaine, or amitriptyline at 2 mg · kg−1 · min−1 (5 mg/mL concentration) or 2) normal saline (400 &mgr;L · kg−1 · min−1) through an external jugular vein cannula. Electrocardiogram and arterial blood pressure were measured until the dose to cause impending death was reached (heart rate 50 bpm/asystole or apnea for >30 s). The mean dose required to cause apnea and impending death was significantly larger for amitriptyline (74.0 ± 21 mg/kg and 74.5 ± 21 mg/kg, respectively) than for levobupivacaine (32.2 ± 20 mg/kg and 33.9 ± 22 mg/kg, respectively) or bupivacaine (21.5 ± 7 mg/kg and 22.7 ± 7 mg/kg, respectively) (P < 0.05). A significantly larger dose of amitriptyline, given by rapid infusion, is required to cause CV and CNS toxicity in rats, when compared with bupivacaine and levobupivacaine.

Doxepin by topical application and intrathecal route in rats.

The tricyclic antidepressant, doxepin, has been reported to be a potent local anesthetic in rat sciatic nerve blockade. We hypothesized that topical doxepin has significantly longer antinociception compared with control and intrathecally compared with bupivacaine. Solutions of 0.3 mL of doxepin at 50, 75, and 100 mM and control (only the vehicle solution) were applied as a patch to the shaved dorsal skin of rats. After a 2-h contact interval, the patch was removed, and the rats were tested by three sets of six pinpricks. Inhibition of withdrawal to pain and cutaneous trunci muscle reflex were graded. In the second investigation, 60 &mgr;L of doxepin at 10, 20, and 50 mM was injected through intrathecal catheters implanted in the lumbar region of rats, which were evaluated for motor function, proprioception, and nociception. Topical doxepin at concentrations of 75 mM and 100 mM was significantly more effective than control (P < 0.05). Complete recovery for the 100-mM concentration occurred at 60 h, although two of five rats demonstrated erythema and scarring. Intrathecally, 20 mM of doxepin was not significantly different for motor and proprioceptive function from 23 mM (0.75%) bupivacaine; however, neurotoxicity (defined as persistent neurological deficit) commenced at 50 mM.

Capnometry in the spontaneously breathing patient.

Purpose of review Capnography has been used in the operating room by anesthesiologists for over a decade. Along with pulse oximetry, it has reduced anesthesia-related morbidity and mortality. Traditionally, capnography has been used to confirm the placement of the endotracheal tube. This review looks into the literature for an update on the use of capnography in the spontaneously breathing patient. Recent findings Several studies support the additional safety afforded by the use of capnography in patients undergoing sedation for procedures in various situations outside the operating room. Capnography has been used as an aid in the diagnosis of pulmonary embolism and sleep-related disorders, as a continuous monitor of metabolic status of pediatric patients with diabetic ketoacidosis and, along with pulse oximetry, in lung-function laboratories to estimate blood gases. Summary Capnography has become a mandatory or recommended monitoring tool in the practice of anesthesiology. It is making inroads into other medical specialties as a monitoring and diagnostic tool. The use of this technology by non-anesthesiologists will continue to increase. In the opinion of the authors capnography should be used in all cases requiring sedation either in or out of the operating room.

Left Atrial Dissection and Intramural Hematoma After Aortic Valve Replacement

Fig 1. LA dissection, left ventricle (LV), LVOT, and aorta (Ao) are visualized in the midesophageal long-axis view after the first AVR. The LA is compressed by the intramural hematoma (white arrows) leading to hypotension. The image is recorded in the process of re-establishing cardiopulmonary bypass. (Color version of figure is available online.)

GlideScope® Tracheal Intubation with and without Muscle Relaxation: A Prospective, Randomized Clinical Trial

Purpose: GlideScope ® videolaryngoscope (GVL, Verathon Medical Inc., Bothell, WA, USA) assisted orotra- cheal intubation is a useful technique for patients who are difficult to intubate, but who can be mask ventilated. The effect of muscle relaxants on the success of GVL intubation has not been evaluated. The authors conducted a prospective, pla- cebo-controlled study to assess the effectiveness and incidence of complications of GVL-assisted tracheal intubation per- formed during general anesthesia with and without the use of a muscle relaxant in patients with seemingly normal airway anatomy. Material and Methods: 52 patients who required orotracheal intubation were prospectively included. Anesthesia was in- duced using midazolam (0.01-0.03 mg/kg), fentanyl (1-3 µg/kg) and propofol (1-3 mg/kg). Patients were randomly as- signed to one of two groups to receive rocuronium 0.6 mg/kg (n = 26 for rocuronium group) or saline intravenously (n = 26 for placebo group). GVL-assisted intubation was initiated after 90 s. The number of successful intubations, the number of attempts and their duration were recorded. Events during the procedure, such as airway trauma, blood pressure changes and movements were also recorded. Results: The success rate of GVL intubation was 100% in the placebo group and 100% in the rocuronium group. Patients in both groups received the same number of intubation attempts and the intubation time were alike (53± 15 vs. 55 ± 18 s; p=0.63). The Placebo group experienced a greater incidence of events during intubation (81 vs. 35%; P < 0.001) than pa- tients in the rocuronium group. Conclusions: Omitting muscle relaxants in patients with apparently normal airways is not associated with a higher failure rate, increased intubation attempts or intubation time when performing GVL assisted orotracheal intubation, but is associ- ated with a higher rate of patient movement.